Coronary heart disease (CHD) has been the leading cause of death in the United States for over a century, and complications from atherosclerosis are the most common causes of death in Western societies (Knopp, New Engl. J. Medicine, 1999, 341, 498-511; Davis and Hui, Arterioscler. Thromb. Vasc. Biol., 2001, 21, 887-898; Bonow, Circulation, 2002, 106, 3140-3141). Elevated low density lipoprotein-cholesterol (LDL-C) is widely recognized as a risk factor for CHD and lowering of LDL-C is highly recommended. However, despite pharmacologic intervention, many individuals are unable to lower LDL-C levels.
Low density lipoproteins (LDL) are one of five broad classes of lipoproteins, which include the following: chylomicrons, responsible for the transport dietary lipids from intestine to tissues; very low density lipoproteins (VLDL); intermediate density lipoproteins (IDL); low density lipoproteins (LDL); all of which transport triacylglycerols and cholesterol from the liver to tissues; and high density lipoproteins (HDL), which transport endogenous cholesterol from tissues to the liver. Lipoprotein particles undergo continuous metabolic processing and have variable properties and compositions. The protein components of lipoproteins are known as apolipoproteins. At least nine apolipoproteins, such as Apolipoprotein B (also known as ApoB, apolipoprotein B-100, ApoB-100, apolipoprotein B-48, ApoB-48 and Ag(x) antigen) and Apolipoprotein C-III (ApoC-III), are distributed in significant amounts among the various human lipoproteins.
ApoB performs a variety of functions, including the absorption and processing of dietary lipids, as well as the regulation of circulating lipoprotein levels (Davidson and Shelness, Annu. Rev. Nutr., 2000, 20, 169-193). Two forms of apolipoprotein B exist in mammals: ApoB-100 and ApoB-48.
ApoC-III is thought to delay catabolism and clearance of triglyceride-rich particles such as VLDL and LDL. Increased ApoC-III levels can induce development of hypertriglyceridemia and ApoC-III concentrations in VLDL and LDL are associated with coronary heart disease (Campos et al., Distinct patterns of lipoproteins with apoB defined by presence of apoE or apoC-III in hypercholesterolemia and hypertriglyceridemia. J. Lipid Res. 2001, 42:1239-1249).
Mipomersen (ISIS 301012), and other second-generation antisense oligonucleotides targeting ApoB-100, have been shown to reduce hepatic production of ApoB. Mipomersen is currently undergoing clinical studies to determine whether it is effective in decreasing LDL-C and triglycerides in specific populations. Although the effect of Mipomersen on ApoB has been studied in detail, its effect, if any, on ApoC-III was unknown.